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Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer.

Lundgren, Katja LU ; Nordenskjöld, B and Landberg, Göran LU (2009) In British Journal of Cancer 101. p.1769-1781
Abstract
Background:Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial-mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer.Methods:Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal... (More)
Background:Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial-mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer.Methods:Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment.Results:Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P=0.048).Conclusions:Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.British Journal of Cancer advance online publication, 20 October 2009; doi:10.1038/sj.bjc.6605369 www.bjcancer.com. (Less)
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type
Contribution to journal
publication status
published
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in
British Journal of Cancer
volume
101
pages
1769 - 1781
publisher
Nature Publishing Group
external identifiers
  • wos:000271666400016
  • pmid:19844232
  • scopus:70449527638
ISSN
1532-1827
DOI
10.1038/sj.bjc.6605369
language
English
LU publication?
yes
id
82c90a34-8484-44df-8c13-b395db8dfafb (old id 1500154)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19844232?dopt=Abstract
date added to LUP
2009-11-03 12:51:16
date last changed
2017-12-10 04:44:18
@article{82c90a34-8484-44df-8c13-b395db8dfafb,
  abstract     = {Background:Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial-mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer.Methods:Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment.Results:Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P=0.048).Conclusions:Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.British Journal of Cancer advance online publication, 20 October 2009; doi:10.1038/sj.bjc.6605369 www.bjcancer.com.},
  author       = {Lundgren, Katja and Nordenskjöld, B and Landberg, Göran},
  issn         = {1532-1827},
  language     = {eng},
  pages        = {1769--1781},
  publisher    = {Nature Publishing Group},
  series       = {British Journal of Cancer},
  title        = {Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer.},
  url          = {http://dx.doi.org/10.1038/sj.bjc.6605369},
  volume       = {101},
  year         = {2009},
}